Experience of a MHRA Inspection Aled Rees Senior Lecturer Centre for Endocrine and Diabetes Sciences

1. Experience of a MHRA Inspection Aled ReesSenior LecturerCentre for Endocrine and Diabetes Sciences

2. Timelines • Trust informed June 2007 • Pre-inspection dossier submitted July 2007 • Informed early October that my trial had been chosen • A Randomised, Double Blind, Placebo-Controlled Study Of The Effects Of Dehydroepiandrosterone Replacement On Vascular Function In Patients With Primary And Secondary Adrenal Insufficiency. Eudract No 2005-000115-10 • SAE list for all trials sent late October • Inspection visit 3rd – 7th December 2007

3. Why me? • MHRA chooses 5-6 trials to inspect • Unlikely a random process and will be chosen to best test the range of systems involved e.g. a multi-centre study, investigator-initiated single centre etc • 1 University-sponsored trial chosen…mine!

4. The weeks leading up to the inspection OR ? • Neither • Plan: • Familiarise myself with all regulations pertaining to clinical trials • Ensure the trial master file was as good as it could be

5. Reference resources accessed • GCP training update (Tanya Symons course) July 2007 • Useful up-to-date information on ICH-GCP, EU Clinical Trials Directive and subsequent amendments, ethics committees, informed consent, pharmacovigilance & reporting requirements etc • National research ethics service (www.nres.npsa.nhs.uk) • MHRA clinical trials (www.mhra.gov.uk) • Draft records management guidance Cardiff University • CU/Trust SOP for trial master file • Cardiff University RACD site SOPs, especially reporting of research related adverse events • Data protection guidance for researchers (Trust guideline) • Clinical trials toolkit website (www.ct-toolkit.ac.uk) • Others

6. The interview • Day 4 Interview 17 – DHEA 3294E • Interviewed in the Clinical Research Facility • 1 and a quarter hours • Present: Me (obviously!), Senior GCP Inspector, Trust R&D Co-ordinator (to take notes) • Co-investigator/nurse not interviewed for my trial but interviewed separately for all others (University sponsored and Trust being inspected)

7. The interview – areas covered • Job history & research experience • GCP training of trial staff and when undertaken (also CVs) • Training in study specific techniques, calibration records discussed • Archiving & retention of data • Where will final data be stored? • Discuss roles and responsibilities of CI and PI (both as a single centre study)

8. The interview – areas covered • Trial set-up – who was involved? (Co-investigators, Clinical Trials Pharmacist, St Mary’s Pharmaceuticals Unit) • Communication with co-investigators • Co-investigator training (certificates in master file) • Trial set-up difficulties – IMP shelf-life/stability issues discussed

9. The interview – areas covered • What is the difference between a substantial and non-substantial amendment? • Any amendments to the study and how dealt with? (change to washout period & approved by sponsor) • I brought up the delay in submission from St Mary’s of a substantial amendment (in relation to batch stability data) – accepted by MHRA but commented upon in inspection report

10. The interview – areas covered • Pharmacovigilance – AE and SAE reporting • What would you do if an SAE occurred? What is an SAE? • Who do you report to? • Timelines of SUSAR reporting etc • What if a co-investigator decided an adverse event had occurred? Could he make a decision? What if CI/PI was on leave? • Could you override co-investigator’s decision? • SOPs for adverse event reporting – Trust v University and Trust incident form also completed

11. The interview – areas covered • Unblinding – emergency and end-of-study • Envelope storage, on-call pharmacist, protocol for emergency unblinding in TMF • Pharmacy issues and St Mary’s – accountability logs, delegation of responsibilities • End of study unblinding ‘SOP’ discussed • Data storage – where held? Identifiable information? Back up. • Source data verification and archiving facilities • End of study statistical plans

12. The interview – areas covered • Trial steering committee? • Risk assessment at study planning • Master file and 5 case notes (list provided by MHRA a week or so before inspection) available for review but I believe may not have been looked at as insufficient time

13. The aftermath • Attended end of inspection report on the Friday afternoon • Trust – 1 critical and 4 major findings later downgraded to 0 critical and 4 major findings

14. The aftermath • Inspection report issued to the Trust February 28th • 11 page summary! • Findings pertaining to DHEA 3294E (Minor/Other) • 3.3.2 Data management and statistics • There was no documented process for database lock and unblinding of blind codes for both …. & DHEA study

15. Conclusions • Do not underestimate the importance of the inspection • Be familiar with all the important regulatory documents • Ensure your site file is spot on • Be honest & remember this is an inspection of systems not really of individual trials • The individual trials are picked to test that appropriate systems are in place and that these are running well

16. Thank you